Progress in Neuro-Psychopharmacology and Biological Psychiatry
Reduced expression of apolipoprotein E receptor type 2 in peripheral blood lymphocytes from patients with major depressive disorder
Introduction
Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide (Ebmeier et al., 2006, Ustün et al., 2004). Evidence implicates the involvement of altered immune response and inflammation in the development of MDD (Irwin and Miller, 2007). Patients with MDD have been reported to show signs of activated innate immune responses as manifested by increased inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6, in the peripheral blood and cerebrospinal fluid (Khairova et al., 2009, Kim et al., 2007, Müller and Ackenheil, 1998, Zorilla et al., 2001). The potential role played by lymphocytes in the adaptive immune response has also been implicated in MDD (Miller, 2010). For instance, T cell responses to mitogens have been shown to be decreased in depressed individuals (Kronfol et al., 1986, Schleifer et al., 1984), and the skin response to commonly encountered antigens as a measure of T cell-mediated immune function is also decreased in patients with MDD (Hickie et al., 1993). Furthermore, the number of B cells in patients with MDD is reported to be decreased as compared to the number in controls (Pavón et al., 2006, Schleifer et al., 1984), although conflicting results have also been reported (Hernandez et al., 2010, Ravindran et al., 1998, Robertson et al., 2005). A decrease in the responsiveness, or possibly the number, of peripheral blood lymphocytes in MDD patients is believed to be related to increased apoptosis (Eilat et al., 1999, Szuster-Ciesielska et al., 2008), although the detailed mechanism of this relationship remains to be elucidated.
Apolipoprotein E (ApoE) is a multifunctional component of plasma lipoproteins (Nimpf and Schneider, 2000). In addition to its functions in lipoprotein metabolism via the low-density lipoprotein (LDL) receptor family, apoE is known to act as an immunomodulator. ApoE is produced by macrophages (Basu et al., 1983, Kockx et al., 2008), which activate T cells by antigen presentation (Mistry et al., 1995, van den Elzen et al., 2005). ApoE has also been implicated in the activation of natural killer T cells by acting as a molecular chaperone for bacterial antigens, delivering them to antigen-presenting cells via LDL receptors (Allan et al., 2009). These findings indicate that apoE and its receptors on lymphocytes are implicated in the adaptive immune responses via intercellular signaling systems. With regard to the LDL receptor family that binds to apoE, apolipoprotein E receptor type 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) are implicated in the pathophysiology of MDD. These receptors bind to reelin, an extracellular matrix glycoprotein that plays crucial roles in brain development as well as in synaptic plasticity in the adult brain (Herz and Chen, 2006). Blood levels of the 180 kD isoform of reelin were shown to be reduced in patients with MDD (Fatemi et al., 2001).
Considering the altered immune responses in MDD and the roles played by apoE and its receptors in the immune system, we hypothesized that the expression of ApoER2 and VLDLR in peripheral blood lymphocytes may be reduced in patients with MDD. To test this, we examined the mRNA expression of ApoER2 and VLDLR in lymphocytes from patients with MDD and matched healthy subjects by quantitative real-time RT-PCR analysis. In addition, we sought to identify relationships between the alteration in mRNA levels of either receptor, if any, and clinical variables in the MDD patients.
Section snippets
Subjects
A total of 86 subjects participated in this study. Forty-three people with MDD (mean [SD] age 39.7 [9.1] years) according to the DSM-IV-TR criteria and 43 age- and gender-matched healthy controls (mean [SD] age 38.8 [6.8] years) were recruited. Twenty-seven patients were either drug-naïve (n = 22) or free from drug treatment for more than 2 months (n = 5) at the sampling (drug-free). Remaining 16 patients were medicated by any psychotropic drug (medicated). The clinical symptoms of patients were
Results
The characteristics of all the participants are summarized in Table 2. Since the difference in age between controls and patients with MDD was not statistically significant (Z = − 1.22, P = 0.22), the age matching was considered to be successful. Out of 16 medicated patients, 13 responded to treatment and entered remission, which was reflected by the medicated patients' lower scores on the HAM-D and BPRS compared to the drug-free patients. The expression levels of the mRNA of ApoER2 and VLDLR in
Discussion
The present study demonstrated that the mRNA levels of ApoER2, but not VLDLR, in peripheral blood lymphocytes from patients with MDD were significantly lower than those of age- and gender-matched healthy control individuals, and that reductions in ApoER2 mRNA levels were significant in both drug-free and medicated patients. These results suggest that the expression of ApoER2 is altered at the transcriptional level in lymphocytes from patients with MDD. The reduction of ApoER2 mRNA levels did
Acknowledgements
This study was supported by a Grant-in-Aid for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to N.M.); this funding had no further role in the study design; in the collection, analysis or interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.
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